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Agonistic ?-Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions.

ABSTRACT: Fibroblast growth factor 21 (FGF21), an endocrine hormone in the FGF family, plays a critical role in regulating metabolic homeostasis and has emerged as a therapeutic target for metabolic diseases, including Type 2 diabetes mellitus. FGF21 functions through a receptor complex that consists of an FGF receptor (FGFR) and a co-receptor ?-Klotho. Here, we identify and biochemically and structurally characterize 39F7, a high-affinity agonistic monoclonal antibody (mAb) against ?-Klotho that mimics FGF21 function. The co-crystal structure of ?-Klotho KL1 domain in complex with 39F7 Fab revealed that the recognition of 39F7 is centered on Trp-295 of ?-Klotho in a FGF21 noncompetitive manner. KL1 adopts a (?/?)8 TIM barrel fold which resembles that of ?-glycosylceramidase, but lacks molecular features for enzymatic activity, suggesting that KL1 functions as a scaffold protein instead. In vitro characterization demonstrated that, although 39F7 does not compete with FGF21, it is specific for ?-Klotho/FGFR1c activation. Furthermore, the agonistic activity of 39F7 required the full IgG molecule to be bivalent, suggesting that 39F7 functions by promoting receptor/co-receptor dimerization. Supported by negative stain EM analysis of full-length ?-Klotho, we propose a molecular model wherein the agonistic antibody 39F7 acts in a ?-Klotho- and FGFR1c-dependent manner, mimicking FGF21 activity. More importantly, 39F7 offers promising therapeutic potential in the axis of FGF21 signaling as an antibody therapy alternative to FGF21 analogs for treatment of metabolic diseases.

SUBMITTER: Min X

PROVIDER: S-EPMC6153294 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Agonistic β-Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions.

Min Xiaoshan X Weiszmann Jennifer J Johnstone Sheree S Wang Wei W Yu Xinchao X Romanow William W Thibault Stephen S Li Yang Y Wang Zhulun Z

The Journal of biological chemistry 20180801 38

Fibroblast growth factor 21 (FGF21), an endocrine hormone in the FGF family, plays a critical role in regulating metabolic homeostasis and has emerged as a therapeutic target for metabolic diseases, including Type 2 diabetes mellitus. FGF21 functions through a receptor complex that consists of an FGF receptor (FGFR) and a co-receptor β-Klotho. Here, we identify and biochemically and structurally characterize 39F7, a high-affinity agonistic monoclonal antibody (mAb) against β-Klotho that mimics F ...[more]

PMID: 30068552

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Project description:UNLABELLED:In animals, high fibroblast growth factor 21 (FGF21) states improve insulin resistance but induce bone loss. Whether FGF21 relates to bone mineral density (BMD) is unknown in humans. Contrary to prediction from animal findings, we found higher FGF21 levels associating with greater BMD in women, independent of age and body composition. INTRODUCTION:Recent laboratory studies suggest that FGF21 is involved in reciprocal regulation of bone and energy homeostasis. Systemic administration of FGF21 protects animals from obesity and diabetes but causes severe bone loss, smothering the enthusiasm over FGF21 as a potential antiobesity therapeutic. To date, there is no information on whether FGF21 relates to BMD in humans. We thus studied the relationship between plasma FGF21 levels and BMD in healthy adults. METHODS:Fasting plasma FGF21 levels were measured by enzyme-linked immunosorbent assay and body composition by dual-energy X-ray absorptiometry. RESULTS:Among 40 healthy volunteers (age 32?±?10 year, 16 women), men had significantly higher lean body mass (p?<?0.01) and total BMD (p?<?0.05), and lower percent body fat than women (p?<?0.01). Median plasma FGF21 levels were not different between the sexes. While there was no association between FGF21 concentrations and body composition in men, FGF21 levels correlated positively with fat mass (p?<?0.01) in women. In men, no significant correlation between FGF21 with BMD was observed. However, in women, FGF21 correlated positively with total BMD (R (2)?=?0.69, p?=?0.003) and spine BMD (R (2)?=?0.76, p?=?0.001); the correlation remained significant after adjusting for age, ethnicity, and body composition. CONCLUSIONS:This study reveals for the first time a strong positive association between plasma FGF21 levels and BMD in healthy women, suggesting the association between bone loss and high FGF21 states in animals may not be directly translated to humans in physiologic states. We hypothesize that FGF21 may increase bone mass particularly in women through paracrine mechanisms in the bone-adipose interface.

Dataset Information

Agonistic ?-Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions.

Publications

Agonistic β-Klotho antibody mimics fibroblast growth factor 21 (FGF21) functions.

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